Retinoic acid (RA) is a well-known antiinflammatory agent. In this study, we show that RA has a dual effect on cyclooxygenase-2 (COX-2) expression in inflammatory activated microglia, the resident brain macrophages. After treatment of microglia with LPS or thrombin, COX-2 expression was induced in two phases, specifically, an initial increase at about 12 hr after stimulation followed by a decrease, and another increase at about 48-72 hr. However, PGE(2) and 15d-PGJ(2) were detected at about 12 hr, and the levels continuously increased thereafter. Interestingly, all-trans retinoic acid (ATRA) suppressed the expression of early-phase COX-2 but augmented late-phase COX-2 and inhibited iNOS in the whole time sequence. ATRA enhanced PGE(2) production but had little effect on 15d-PGJ(2). Moreover, ATRA selectively up-regulated the expression of a PGE(2) synthase, mPGES-1, but had little effect on the PGD(2) synthase, H-PGDS. The results collectively suggest that ATRA modulates microglial responses to inflammatory stimulators, particularly at the late phase, via enhancement of COX-2 expression and PGE(2) production.